text: AR activation requires the formation of a functional activation function 2 (AF2) region in AR LBD that mediates the interactions between AR and various transcription cofactors. Therefore, most of the research on NTD AR antagonists focuses on peptides that may directly block the AF2 in AR LBD from protein surface. Even in bound mutant AR, NTD antagonists would be able to block the AF2 function via direct surface interaction, regardless of the ligand bound.
  Research on these NTD antagonists are usually carried out by affinity screening of phage display libraries that express random peptides containing various signature motifs. ARs seem to have a distinct preference for ‘FxxLF’ type of binding motifs (where F = phenylalanine, L = leucine, and X = any amino acid residue), whereas other nuclear receptors have a highly similar binding mechanism for ‘LxxLL’ type of binding motifs. This provides a unique opportunity for the development of AR-specific peptides.
  Even though small molecule antagonists and NTD antagonist targeting AF2 surface differ in binding sites, they both inhibit AR function by disrupting AF2 function. Therefore, mechanistically, these NTD antagonists may also be classified as ‘AF2 antagonists’.